This proposal presents a series of focused studies to further elucidate the molecular basis for S phase specific transcription of histone genes, and to determine whether these mechanisms pertain in the regulation of chromosomal DNA synthesis. The ultimate aim of this work is to gain a molecular understanding of the transition from G1 to S phase, and to identify specific targets for intervention of cell growth at this point in the cell cycle. The experimental emphasis in this proposal is based on fundamental insights into this process gained during the last five years of this grant, and will focus upon six specific aims: 1) further characterization of the histone gene subtype specific cell cycle regulatory proteins OTF1, H1TF2, H1TF1 and H4TF2, 2) identification of enzymes involved in cell cycle regulated modification of OTF1, and demonstration that post- translational modification of OTF1 is functionally important for H2b transcription, 3) exploration of the regulation of H1TF2 (and ultimately H1TF1 and H4TF2) activity during the cell cycle to test whether the mechanisms regulating OTF1 are pleiotropic, 4) biochemical and genetic analysis of S. cerevisiae S phase specific histone gene transcriptional control, 5) analysis of the putative replication initiation factors RIP60 and RIP100 as potential substrates for the S phase regulatory mechanisms involved in transcriptional control, 6) analysis of upstream regulatory molecules in the pathway leading to activation of S phase specific transcription (e.g. protein phosphatase IIa, etc). These studies will result in identification of fundamental cell cycle regulatory mechanisms which may result in opportunities to specifically intervene in cell growth.